The present invention is directed to a process for the preparation of (+)-(2R)-endo-norborneol and (-)-(2S)-endo-norborneol, and for their further conversion, respectively, to the pharmaceutical agents 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxy-phenyl)-3,4,5,6-tetra hydropyrimidin-2(1H)-one, of the formula ##STR1## and its enantomer, 5-(3-[2R)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahy dropyrimidin-2(1H)-one, of the formula ##STR2## The present invention is also directed to these particular optically active pharmaceutical agents per se, and to intermediates [of the formulas (III) to (VI) below] used in their synthesis.
(2R)-endo-Norborneol is alternatively named (2R)-endo-bicyclo[2.2.1]heptan-2-ol or (1S,2R,4R)bicyclo[2.2.1]heptan-2-ol. Likewise, enantiomeric (2S)-endo-norborneol is alternatively named (2S)-endo-bicyclo[2.2.1]heptan-2-ol or (1R,2S,4S)-bicyclo[2.2.1]heptan-2-ol. Analogously, derived (2S)-exo-bicyclo[2.2.1]hept-2-yl and (2R)-exo-bicyclo[2.2.1]hept-2-yl substituent groups are alternatively named, respectively, (1S,2S,4R)-bicyclo[2.2.1]hept-2-yl and (1R,2R,4S)-bicyclo[2.2.1]hept-2-yl.
The present compounds of the formulas (I) and (II) represent particularly valuable species of the compounds broadly disclosed by Saccomano, et al. in published International Patent Application W087/06576, having utility as antidepressants. Although that reference specifically discloses racemic 5-(3-[(2S)-exo-bicyclo[2.2.1] hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, there is no specific disclosure of the present optically active variants thereof, or of any specific method for their preparation. As further disclosed hereinbelow, and in the concurrently filed International Patent Application No. PCT/US89/00000 [Docket no. 7641/PH], the present compounds of the formulas (I) and (II) are also particularly valuable in the treatment of asthma and certain skin disorders.
Heretofore, optically active (2R)-and (2S)-endo-norborneols were obtained by resolution of racemic exo-norborneol hemiphthalate ester with optically active phenethylamines, hydrolysis to optically active exo-norborneols, CRO.sub.3 oxidation to optically active norbornanones and finally Li(s-Bu).sub.3 BH reduction to the desired endo-isomers. Irwin et al., J. Am. Chem. Soc., v. 98, pp. 8,476-8,481 (1979). According to the same reference, enantomeric enrichment of endo-norborneols was achieved by incomplete horse liver alcohol dehydrogenase catalyzed reduction of racemic 2-norbornanone; while incomplete oxidation of racemic exo-norborneol catalyzed by the same enzyme gave enantiomerically enriched exo-norborneols. (-)-exo-Norborneol has also been prepared from norbornene by asymmetric hydroboration, Brown, et al., J. Org. Chem, v. 47, pp. 5,065-5,069 (1982).
Heretofore, certain chiral alcohols have been resolved using transesterification catalyzed by porcine pancreatic lipase in a nearly anhydrous organic solvent. Kirchner, et al., J. Am. Chem. Soc. v. 107, pp. 7,072-7,076 (1985). For example, 47% conversion of racemic 2-octanol and 2,2,2-trichloroethyl butyrate gave (R)-2-octyl butyrate of high optical purity. However, when this method was applied to racemic exo-norborneol, both the recovered alcohol and the product butyrate ester remained essentially racemic, even though the transesterification was definitely enzyme mediated (as shown by lack of reaction absent the enzyme).